CONTROL OF ALPHAVIRUS REPLICATION IN THE NERVOUS SYSTEM

神经系统中甲病毒复制的控制

• 批准号: 6771788
• 负责人: Diane E Griffin
• 金额: $ 31.75万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6771788
• 关键词: SCID mouse; Sindbis virus; antigen antibody reaction; cytokine; disease /disorder model; encephalitis; enzyme activity; flow cytometry; glycoproteins; host organism interaction; infectious encephalomyelitis; interferons; latent virus infection; microorganism metabolism; neurotropic virus; protein localization; protein structure function; sodium potassium exchanging ATPase; virus protein; virus replication; voltage /patch clamp

DESCRIPTION: Sindbis virus (SV) is an alphavirus that infects neurons and causes acute encephalomyelitis in mice. Non-fatal SV infection of the central nervous system (CNS) of weanling mice elicits a well-characterized immune response and provides a model system for studying mechanisms by which virus is cleared from neural cells. Mice with severe combined immunodeficiency (SCID) cannot clear virus and these mice develop persistent infection. The applicant has shown by passive transfer experiments that antibody (Ab) is the primary mechanism by which infectious virus is cleared from the CNS. Ab-mediated control of intracellular virus replication is independent of complement and leukocytes, is noncytolytic and requires cross-linking of the E2 glycoprotein on the surface of the infected cell. Downregulation of SV replication is associated with improved Na+K+ATPase-dependent control of cation flux and results in restoration of host protein synthesis and response to type 1 interferons (IFNs). In mice this noncytotoxic mechanism for control of virus replication results in persistence of viral RNA in the CNS and long-term local production of antiviral Ab by B cells in the CNS. In the current application, the applicant proposes to determine the mechanism by which Ab controls intracellular virus replication in vivo and in vitro and the role of IFN in this process through the following specific aims: (1) To define the required specificity and cellular localization of antibody for effective control of intracellular SV replication; (2) To determine the mechanism by which antibody to the E2 glycoprotein of SV restores Na+K+ATPase function and controls intracellular virus replication; (3) To determine the relative roles of antibody, interferon and T cell cytokines for in vivo control of SV replication.

描述：信德比斯病毒（SV）是一种感染神经元和的α病毒 导致小鼠急性脑脊髓炎。中央的非致命SV感染 断奶小鼠的神经系统（CNS）引起了特征良好的免疫 响应并提供了一个模型系统，用于研究病毒是的机制 从神经细胞中清除。严重合并免疫缺陷（SCID）的小鼠 无法清除病毒，这些小鼠会发展出持续的感染。申请人 通过被动转移实验表明抗体（AB）是主要的 从中枢神经系统中清除传染病的机制。 AB介导的 控制细胞内病毒复制独立于补体和 白细胞是非溶解的，需要E2糖蛋白的交联 在感染细胞的表面。 SV复制的下调是 与改善阳离子通量的Na+K+ATPase依赖性控制有关 导致恢复宿主蛋白的合成和对1型的反应 干扰素（IFNS）。在小鼠中，这种控制病毒的非毒性机制 复制导致中枢神经系统中病毒RNA的持久性和长期局部 中枢神经系统中B细胞生产抗病毒AB。在当前的应用程序中 申请人建议确定AB控制的机制 细胞内病毒在体内和体外复制以及IFN在 通过以下特定目的进行此过程：（1）定义所需的 抗体的特异性和细胞定位，以有效控制 细胞内SV复制； （2）确定抗体的机制 到SV的E2糖蛋白恢复Na+K+ATPase函数和控制 细胞内病毒复制； （3）确定 抗体，干扰素和T细胞细胞因子在体内控制SV 复制。